Methods of making sustained release formulations of oxymorphone

ABSTRACT

Sustained release formulations of oxymorphone or pharmaceutically acceptable salts thereof; methods for making the sustained release formulations of oxymorphone or pharmaceutically acceptable salts thereof; and methods for using the sustained release formulations of oxymorphone or pharmaceutically acceptable salts thereof to treat patients suffering from pain are provided.

RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional ApplicationNo. 60/329,352 filed Oct. 15, 2001, U.S. Provisional Application No.60/329,426 filed Oct. 15, 2001, and to U.S. Provisional Application No.60/303,357 filed Jul. 6, 2001, the disclosures of which are incorporatedby reference herein in their entirety.

FIELD OF THE INVENTION

[0002] The invention provides sustained release formulations ofoxymorphone and pharmaceutically acceptable salts thereof; methods formaking the sustained release formulations of oxymorphone andpharmaceutically acceptable salts thereof; and methods for using thesustained release formulations of oxymorphone and pharmaceuticallyacceptable salts thereof to treat patients suffering from pain.

BACKGROUND OF THE INVENTION

[0003] Pain is the most frequently reported symptom and it is a commonclinical problem which confronts the clinician. Many millions of peoplein the United States suffer from severe pain that is chronicallyundertreated or inappropriately managed. The clinical usefulness of theanalgesic properties of opioids has been recognized for centuries, andmorphine and its derivatives have been widely used for analgesia fordecades in a variety of clinical pain states.

[0004] Oxymorphone HCl (14-hydroxydihydromorphinone hydrochloride) is asemi-synthetic phenanthrene-derivative opioid agonist, used in thetreatment of acute and chronic pain, with analgesic efficacy comparableto other opioid analgesics. Oxymorphone is currently marketed as aninjection (1 mg/ml in 1 ml ampules; 1.5 mg/ml in 1 ml ampules; 1.5 mg/mlin 10 ml multiple dose vials) for intramuscular, subcutaneous, andintravenous administration, and as 5 mg rectal suppositories. At onetime, a 10 mg oral immediate release tablet formation of oxymorphone HClwas marketed. Oxymorphone HCl is metabolized principally in the liverand undergoes conjugation with glucuronic acid and reduction to 6 alphaand beta hydroxy epimers.

[0005] An important goal of analgesic therapy is to achieve continuousrelief of chronic pain. Regular administration of an analgesic isgenerally required to ensure that the next dose is given before theeffects of the previous dose have worn off. Compliance with opioidsincreases as the required dosing frequency decreases. Non-complianceresults in suboptimal pain control and poor quality of life outcomes.Scheduled rather than “as needed” administration of opioids is currentlyrecommended in guidelines for their use in treating chronicnon-malignant pain. Unfortunately, evidence from prior clinical trialsand clinical experience suggests that the short duration of action ofimmediate release oxymorphone would necessitate 4-hourly administrationsin order to maintain optimal levels of analgesia in patients withchronic pain. Moreover, immediate release oxymorphone exhibits low oralbioavailability, because oxymorphone is extensively metabolized in theliver.

[0006] There is a need in the art for new formulations of oxymorphonerequire less frequent dosing. The invention is directed to these, aswell as other, important ends.

SUMMARY OF THE INVENTION

[0007] The invention provides compositions comprising oxymorphone or apharmaceutically acceptable salt thereof and a sustained releasedelivery system, where the sustained release delivery system comprisesat least one hydrophilic compound, at least one cross-linking agent(which may be cationic) and at least one pharmaceutical diluent. Thesustained release delivery system may further comprise one or moreadditional hydrophobic polymers or cross-linking compounds. Thecompositions may optionally comprise an outer coating comprising atleast one water insoluble compound, and optionally one or moreplasticizers and/or water soluble compounds.

[0008] The invention provides compositions comprising an inner core andan outer sustained release coating, where the inner core comprisesoxymorphone or a pharmaceutically acceptable salt thereof and the outersustained release coating comprises at least one water insolublecompound. The outer sustained release coating may optionally furthercomprise one or more plasticizers and/or water soluble compounds.

[0009] The invention provides methods for treating pain in patients byadministering an effective amount of any of the compositions of theinvention. The pain may be moderate to severe, and may be acute orchronic.

[0010] The invention also provides methods for making such compositions.

[0011] These and other aspects of the invention are described in detailherein.

BRIEF DESCRIPTION OF THE FIGURE

[0012]FIG. 1 is a linear scale graph, without standard deviations,showing the mean oxymorphone plasma concentration versus time forpatients treated with the sustained release oxymorphone tablets of theinvention after fasting (A), for patients treated with sustained releaseoxymorphone tablets of the invention after a high fat meal (B), forpatients treated with an oxymorphone solution after fasting (C), and forpatients treated with an oxymorphone solution after a high fat meal (D).

DETAILED DESCRIPTION OF THE INVENTION

[0013] To overcome the difficulties associated with the very lowbioavailability of the oral immediate release formulation of oxymorphoneand with a 4 hourly dosing frequency of oxymorphone, the inventionprovides an oral sustained release formulation of oxymorphone comprisingan analgesically effective amount of oxymorphone or a pharmaceuticallyacceptable salt thereof. The bioavailability of the oral sustainedrelease formulations of the invention is sufficiently high that thesustained release formulations can be used to treat patients sufferingfrom pain with only once or twice daily dosing.

[0014] The invention provides compositions comprising oxymorphone or apharmaceutically acceptable salt thereof and a sustained releasedelivery system, wherein the sustained release delivery system comprises(i) at least one hydrophilic compound, at least one cross-linking agent,and at least one pharmaceutical diluent; (ii) at least one hydrophiliccompound, at least one cross-linking agent, at least one pharmaceuticaldiluent, and at least one hydrophobic polymer; (iii) at least onehydrophilic compound, at least one cross-linking agent, at least onepharmaceutical diluent, and at least one cationic cross-linking agentdifferent from the first cross-linking agent; (iv) at least onehydrophilic compound, at least one cross-linking agent, at least onepharmaceutical diluent, at least one cationic cross-linking compounddifferent from the first cross-linking agent, and at least onehydrophobic polymer; (v) at least one hydrophilic compound, at least onecationic cross-linking compound, and at least one pharmaceuticaldiluent; or (vi) at least one hydrophilic compound, at least onecationic cross-linking compound, at least one pharmaceutical diluent,and at least one hydrophobic compound.

[0015] The oxymorphone may be homogeneously dispersed in the sustainedrelease delivery system. Preferably, the oxymorphone or pharmaceuticallyacceptable salt thereof may be present in the composition in an amountof about 1 mg to about 200 mg, more preferably in an amount of about 1mg to about 100 mg, even more preferably in an amount of about 5 mg toabout 80 mg. Preferably, the sustained release delivery system may bepresent in the composition in an amount from about 80 mg to about 420mg, more preferably from about 80 mg to about 360 mg, even morepreferably from about 80 mg to about 200 mg. “Oxymorphone” includesoxymorphone, metabolites thereof, derivatives thereof, and/orpharmaceutically acceptable salts thereof. Metabolites of oxymorphoneinclude, for example, 6-hydroxy-oxymorphone (e.g.,6-α-hydroxy-oxymorphone and/or 6-β-hydroxy-oxymorphone).

[0016] Oxymorphone may be in the form of any pharmaceutically acceptablesalt known in the art. Exemplary pharmaceutically acceptable saltsinclude hydrochloric, sulfuric, nitric, phosphoric, hydrobromic,maleric, malic, ascorbic, citric, tartaric, pamoic, lauric, stearic,palmitic, oleic, myristic, lauryl sulfuric, napthalinesulfonic,linoleic, linolenic acid, and the like. The hydrochloride salt ofoxymorphone is preferred.

[0017] The sustained release delivery system comprises at least onehydrophilic compound. The hydrophilic compound preferably forms a gelmatrix that releases the oxymorphone or the pharmaceutically acceptablesalt thereof at a sustained rate upon exposure to liquids. The rate ofrelease of the oxymorphone or the pharmaceutically acceptable saltthereof from the gel matrix depends on the drug's partition coefficientbetween the components of the gel matrix and the aqueous phase withinthe gastrointestinal tract. In the compositions of the invention, theweight ratio of oxymorphone to hydrophilic compound is generally in therange of about 1:0.5 to about 1:25, preferably in the range of about1:0.5 to about 1:20. The sustained release delivery system generallycomprises the hydrophilic compound in an amount of about 20% to about80% by weight, preferably in an amount of about 20% to about 60% byweight, more preferably in an amount of about 40% to about 60% byweight, still more preferably in an amount of about 50% by weight.

[0018] The hydrophilic compound may be any known in the art. Exemplaryhydrophilic compounds include gums, cellulose ethers, acrylic resins,polyvinyl pyrrolidone, protein-derived compounds, and mixtures thereof.Exemplary gums include heteropolysaccharide gums and homopolysaccharidegums, such as xanthan, tragacanth, pectins, acacia, karaya, alginates,agar, guar, hydroxypropyl guar, carrageenan, locust bean gums, andgellan gums. Exemplary cellulose ethers include hydroxyalkyl cellulosesand carboxyalkyl celluloses. Preferred cellulose ethers includehydroxyethyl celluloses, hydroxypropyl celluloses,hydroxypropylmethyl-celluloses, carboxy methylcelluloses, and mixturesthereof. Exemplary acrylic resins include polymers and copolymers ofacrylic acid, methacrylic acid, methyl acrylate and methyl methacrylate.In some embodiments, the hydrophilic compound is preferably a gum, morepreferably a heteropolysaccharide gum, most preferably a xanthan gum orderivative thereof. Derivatives of xanthan gum include, for example,deacylated xanthan gum, the carboxymethyl esters of xanthan gum, and thepropylene glycol esters of xanthan gum.

[0019] In another embodiment, the sustained release delivery system mayfurther comprise at least one cross-linking agent. The cross-linkingagent is preferably a compound that is capable of cross-linking thehydrophilic compound to form a gel matrix in the presence of liquids. Asused herein, “liquids” includes, for example, gastrointestinal fluidsand aqueous solutions, such as those used for in vitro dissolutiontesting. The sustained release delivery system generally comprises thecross-linking agent in an amount of about 0.5% to about 80% by weight,preferably in an amount of about 2% to about 54% by weight, morepreferably in an amount of about 20% to about 30% by weight more, stillmore preferably in an amount of about 25% by weight.

[0020] Exemplary cross-linking agents include homopolysaccharides.Exemplary homopolysaccharides include galactomannan gums, such as guargum, hydroxypropyl guar gum, and locust bean gum. In some embodiments,the cross-linking agent is preferably a locust bean gum or a guar gum.In other embodiments, the cross-linking agents may be alginic acidderivatives or hydrocolloids.

[0021] When the sustained release delivery system comprises at least onehydrophilic compound and at least one cross-linking agent, the ratio ofhydrophilic compound to cross-linking agent may be from about 1:9 toabout 9:1, preferably from about 1:3 to about 3:1.

[0022] The sustained release delivery system of the invention maycomprise one or more cationic cross-linking compounds. Cationiccross-linking compound may be used instead of or in addition to thecross-linking agent. The cationic cross-linking compounds may be used inan amount sufficient to cross-link the hydrophilic compound to form agel matrix in the presence of liquids. The cationic cross-linkingcompound is present in the sustained release delivery system in anamount of about 0.5% to about 30% by weight, preferably from about 5% toabout 20% by weight.

[0023] Exemplary cationic cross-linking compounds include monovalentmetal cations, multivalent metal cations, and inorganic salts, includingalkali metal and/or alkaline earth metal sulfates, chlorides, borates,bromides, citrates, acetates, lactates, and mixtures thereof. Forexample, the cationic cross-linking compound may be one or more ofcalcium sulfate, sodium chloride, potassium sulfate, sodium carbonate,lithium chloride, tripotassium phosphate, sodium borate, potassiumbromide, potassium fluoride, sodium bicarbonate, calcium chloride,magnesium chloride, sodium citrate, sodium acetate, calcium lactate,magnesium sulfate, sodium fluoride, or mixtures thereof.

[0024] When the sustained release delivery system comprises at least onehydrophilic compound and at least one cationic cross-linking compound,the ratio of hydrophilic compound to cationic cross-linking compound maybe from about 1:9 to about 9:1, preferably from about 1:3 to about 3:1.

[0025] Two properties of desirable components of this system (e.g., theat least one hydrophilic compound and the at least one cross-linkingagent; or the at least one hydrophilic compound and at least onecationic cross-linking compound) that form a gel matrix upon exposure toliquids are fast hydration of the compounds/agents and the ability toform a gel matrix having a high gel strength. These two properties,which are needed to achieve a slow release gel matrix, are maximized inthe invention by the particular combination of compounds (e.g., the atleast one hydrophilic compound and the at least one cross-linking agent;or the at least one hydrophilic compound and the at least one cationiccross-linking compound). For example, hydrophilic compounds (e.g.,xanthan gum) have excellent water-wicking properties which provide fasthydration. The combination of hydrophilic compounds with materials thatare capable of cross-linking the rigid helical ordered structure of thehydrophilic compound (e.g., cross-linking agents and/or cationiccross-linking compounds) thereby act synergistically to provide a higherthan expected viscosity (i.e., high gel strength) of the gel matrix.

[0026] The sustained release delivery system further comprises one ormore pharmaceutical diluents known in the art. Exemplary pharmaceuticaldiluents include monosaccharides, disaccharides, polyhydric alcohols andmixtures thereof. Preferred pharmaceutical diluents include, forexample, starch, lactose, dextrose, sucrose, microcrystalline cellulose,sorbitol, xylitol, fructose, and mixtures thereof. In other embodiments,the pharmaceutical diluent is water-soluble, such as lactose, dextrose,sucrose, or mixtures thereof. The ratio of pharmaceutical diluent tohydrophilic compound is generally from about 1:8 to about 8:1,preferably from about 1:3 to about 3:1. The sustained release deliverysystem generally comprises one or more pharmaceutical diluents in anamount of about 20% to about 80% by weight, preferably about 35% byweight. In other embodiments, the sustained release delivery systemcomprises one or more pharmaceutical diluents in an amount of about 40%to about 80% by weight.

[0027] The sustained release delivery system of the invention maycomprise one or more hydrophobic polymers. The hydrophobic polymers maybe used in an amount sufficient to slow the hydration of the hydrophiliccompound without disrupting it. For example, the hydrophobic polymer maybe present in the sustained release delivery system in an amount ofabout 0.5% to about 20% by weight, preferably in an amount of about 2%to about 10% by weight, more preferably in an amount of about 3% toabout 7% by weight, still more preferably in an amount of about 5% byweight.

[0028] Exemplary hydrophobic polymers include alkyl celluloses (e.g.,C₁₋₆ alkyl celluloses, carboxymethylcellulose), other hydrophobiccellulosic materials or compounds (e.g., cellulose acetate phthalate,hydroxypropylmethylcellulose phthalate), polyvinyl acetate polymers(e.g., polyvinyl acetate phthalate), polymers or copolymers derived fromacrylic and/or methacrylic acid esters, zein, waxes, shellac,hydrogenated vegetable oils, and mixtures thereof. The hydrophobicpolymer is preferably methyl cellulose, ethyl cellulose or propylcellulose, more preferably ethyl cellulose.

[0029] The compositions of the invention may be further admixed with oneor more wetting agents (such as polyethoxylated castor oil,polyethoxylated hydrogenated castor oil, polyethoxylated fatty acid fromcastor oil, polyethoxylated fatty acid from hydrogenated castor oil) oneor more lubricants (such as magnesium stearate), one or more bufferingagents, one or more colorants, and/or other conventional ingredients.

[0030] In other embodiments, the invention provides oral sustainedrelease solid dosage formulations comprising from about 1 mg to 200 mgoxymorphone hydrochloride, preferably from about 5 mg to about 80 mgoxymorphone hydrochloride; and about 80 mg to about 200 mg of asustained release delivery system, preferably from about 120 mg to about200 mg of a sustained release delivery system, more preferably about 160mg of a sustained release delivery system; where the sustained releasedelivery system comprises about 8.3 to about 41.7% locust bean gum,preferably about 25% locust bean gum; about 8.3 to about 41.7% xanthangum, preferably about 25% xanthan gum; about 20 to about 55% dextrose,preferably about 35% dextrose; about 5 to about 20% calcium sulfatedihydrate, preferably about 10% calcium sulfate dihydrate; and about 2to 10% ethyl cellulose, preferably about 5% ethyl cellulose.

[0031] In other embodiments, the invention provides oral sustainedrelease solid dosage formulations comprising from about 1 mg to 200 mgoxymorphone hydrochloride, preferably from about 5 mg to about 80 mgoxymorphone hydrochloride; and about 200 mg to about 420 mg of asustained release delivery system, preferably from about 300 mg to about420 mg of a sustained release delivery system, more preferably about 360mg of a sustained release delivery system; where the sustained releasedelivery system comprises about 8.3 to about 41.7% locust bean gum,preferably about 25% locust bean gum; about 8.3 to about 41.7% xanthangum, preferably about 25% xanthan gum; about 20 to about 55% dextrose,preferably about 35% dextrose; about 5 to about 20% calcium sulfatedihydrate, preferably about 10% calcium sulfate dihydrate; and about 2to 10% ethyl cellulose, preferably about 5% ethyl cellulose.

[0032] The sustained release formulations of oxymorphone are preferablyorally administrable solid dosage formulations which may be, forexample, tablets, capsules comprising a plurality of granules,sublingual tablets, powders, or granules; preferably tablets. Thetablets may be an enteric coating or a hydrophilic coating.

[0033] The sustained release delivery system in the compositions of theinvention may be prepared by dry granulation or wet granulation, beforethe oxymorphone or pharmaceutically acceptable salt thereof is added,although the components may be held together by an agglomerationtechnique to produce an acceptable product. In the wet granulationtechnique, the components (e.g., hydrophilic compounds, cross-linkingagents, pharmaceutical diluents, cationic cross-linking compounds,hydrophobic polymers, etc.) are mixed together and then moistened withone or more liquids (e.g., water, propylene glycol, glycerol, alcohol)to produce a moistened mass which is subsequently dried. The dried massis then milled with conventional equipment into granules of thesustained release delivery system. Thereafter, the sustained releasedelivery system is mixed in the desired amounts with the oxymorphone orthe pharmaceutically acceptable salt thereof and, optionally, one ormore wetting agents, one or more lubricants, one or more bufferingagents, one or more coloring agents, or other conventional ingredients,to produce a granulated composition. The sustained release deliverysystem and the oxymorphone may be blended with, for example, a highshear mixer. The oxymorphone is preferably finely and homogeneouslydispersed in the sustained release delivery system. The granulatedcomposition, in an amount sufficient to make a uniform batch of tablets,is subjected to tableting in a conventional production scale tabletingmachine at normal compression pressures, i.e., about 2,000-16,000 psi.The mixture should not be compressed to a point where there issubsequent difficulty with hydration upon exposure to liquids.

[0034] The average particle size of the granulated composition is fromabout 50 μm to about 400 μm, preferably from about 185 μm to about 265μm. The average density of the granulated composition is from about 0.3g/ml to about 0.8 μg/ml, preferably from about 0.5 g/ml to about 0.7g/ml. The tablets formed from the granulations are generally from about6 to about 8 kg hardness. The average flow of the granulations are fromabout 25 to about 40 g/sec.

[0035] In other embodiments, the invention provides sustained releasecoatings over an inner core comprising oxymorphone or a pharmaceuticallyacceptable salt thereof. For example, the inner core comprisingoxymorphone or a pharmaceutically acceptable salt thereof may be coatedwith a sustained release film which, upon exposure to liquids, releasesthe oxymorphone or the pharmaceutically acceptable salt thereof from thecore at a sustained rate.

[0036] In one embodiment, the sustained release coating comprises atleast one water insoluble compound. The water insoluble compound ispreferably a hydrophobic polymer. The hydrophobic polymer may be thesame as or different from the hydrophobic polymer used in the sustainedrelease delivery system. Exemplary hydrophobic polymers include alkylcelluloses (e.g., C₁₋₆ alkyl celluloses, carboxymethylcellulose), otherhydrophobic cellulosic materials or compounds (e.g., cellulose acetatephthalate, hydroxypropylmethylcellulose phthalate), polyvinyl acetatepolymers (e.g., polyvinyl acetate phthalate), polymers or copolymersderived from acrylic and/or methacrylic acid esters, zein, waxes (aloneor in admixture with fatty alcohols), shellac, hydrogenated vegetableoils, and mixtures thereof. The hydrophobic polymer is preferably,methyl cellulose, ethyl cellulose or propyl cellulose, more preferablyethyl cellulose. The sustained release formulations of the invention maybe coated with a water insoluble compound to a weight gain from about 1to about 20% by weight.

[0037] The sustained release coating may further comprise at least oneplasticizer such as triethyl citrate, dibutyl phthalate, propyleneglycol, polyethylene glycol, or mixtures thereof.

[0038] The sustained release coating may also contain at least one watersoluble compound, such as polyvinylpyrrolidones,hydroxypropylmethylcelluloses, or mixtures thereof. The sustainedrelease coating may comprise at least one water soluble compound in anamount from about 1% to about 6% by weight, preferably in an amount ofabout 3% by weight.

[0039] The sustained release coating may be applied to the oxymorphonecore by spraying an aqueous dispersion of the water insoluble compoundonto the oxymorphone core. The oxymorphone core may be a granulatedcomposition made, for example, by dry or wet granulation of mixedpowders of oxymorphone and at least one binding agent; by coating aninert bead with oxymorphone and at least one binding agent; or byspheronizing mixed powders of oxymorphone and at least one spheronizingagent. Exemplary binding agents include hydroxypropylmethylcelluloses.Exemplary spheronizing agents include microcrystalline celluloses. Theinner core may be a tablet made by compressing the granules or bycompressing a powder comprising oxymorphone or the pharmaceuticallyacceptable salt thereof.

[0040] In other embodiments, the compositions comprising oxymorphone ora pharmaceutically acceptable salt thereof and a sustained releasedelivery system, as described herein, are coated with a sustainedrelease coating, as described herein. In still other embodiments, thecompositions comprising oxymorphone or a pharmaceutically acceptablesalt thereof and a sustained release delivery system, as describedherein, are coated with a hydrophobic polymer, as described herein. Instill other embodiments, the compositions comprising oxymorphone or apharmaceutically acceptable salt thereof and a sustained releasedelivery system, as described herein, are coated with an entericcoating, such as cellulose acetate phthalate,hydroxypropylmethylcellulose phthalate, polyvinylacetate phthalate,methacrylic acid copolymer, shellac, hydroxypropylmethylcellulosesuccinate, cellulose acetate trimelliate, or mixtures thereof. In stillother embodiments, the compositions comprising oxymorphone or apharmaceutically acceptable salt thereof and a sustained releasedelivery system, as described herein, are coated with a hydrophobicpolymer, as described herein, and further coated with an entericcoating, as described herein. In any of the embodiments describedherein, the compositions comprising oxymorphone or a pharmaceuticallyacceptable salt thereof and a sustained release delivery system, asdescribed herein, may optionally be coated with a hydrophilic coatingwhich may be applied above or beneath the sustained release film, aboveor beneath the hydrophobic coating, and/or above or beneath the entericcoating. Preferred hydrophilic coatings comprisehydroxypropylmethylcellulose.

[0041] The invention provides methods for treating pain by administeringan effective amount of the sustained release formulations of oxymorphoneto a patient in need thereof. An effective amount is an amountsufficient to eliminate all pain or to alleviate the pain (i.e., reducethe pain compared to the pain present prior to administration of theoxymorphone sustained release formulation). “Sustained release” meansthat the oxymorphone or pharmaceutically acceptable salt thereof isreleased from the formulation at a controlled rate so thattherapeutically beneficial blood levels (but below toxic levels) of theoxymorphone or pharmaceutically acceptable salt thereof are maintainedover an extended period of time. The sustained release formulations ofoxymorphone are administered in an amount sufficient to alleviate painfor an extended period of time, preferably about 8 hours to about 24hours, more preferably for a period of about 12 hours to about 24 hours.The oxymorphone sustained release oral solid dosage formulations of theinvention may be administered one to four times a day, preferably onceor twice daily, more preferably once daily. The pain may be minor tomoderate to severe, and is preferably moderate to severe. The pain maybe acute or chronic. The pain may be associated with, for example,cancer, autoimmune diseases, infections, surgical traumas, accidentaltraumas or osteoarthritis. The patient may be an animal, preferably amammal, more preferably a human.

[0042] In certain embodiments, upon oral ingestion of the oxymorphonesustained release formulation and contact of the formulation withgastrointestinal fluids, the sustained release formulation swells andgels to form a hydrophilic gel matrix from which the oxymorphone isreleased. The swelling of the gel matrix causes a reduction in the bulkdensity of the formulation and provides the buoyancy necessary to allowthe gel matrix to float on the stomach contents to provide a slowdelivery of the oxymorphone. The hydrophilic matrix, the size of whichis dependent upon the size of the original formulation, can swellconsiderably and become obstructed near the opening of the pylorus.Since the oxymorphone is dispersed throughout the formulation (andconsequently throughout the gel matrix), a constant amount ofoxymorphone can be released per unit time in vivo by dispersion orerosion of the outer portions of the hydrophilic gel matrix. The processcontinues, with the gel matrix remaining bouyant in the stomach, untilsubstantially all of the oxymorphone is released.

[0043] In certain embodiments, the chemistry of certain of thecomponents of the formulation, such as the hydrophilic compound (e.g.,xanthan gum), is such that the components are considered to beself-buffering agents which are substantially insensitive to thesolubility of the oxymorphone and the pH changes along the length of thegastrointestinal tract. Moreover, the chemistry of the components isbelieved to be similar to certain known muco-adhesive substances, suchas polycarbophil. Muco-adhesive properties are desirable for buccaldelivery systems. Thus, the sustained release formulation can looselyinteract with the mucin in the gastrointestinal tract and therebyprovide another mode by which a constant rate of delivery of theoxymorphone is achieved.

[0044] The two phenomenon discussed above (buoyancy and muco-adhesiveproperties) are mechanisms by which the sustained release formulationsof the invention can interact with the mucin and fluids of thegastrointestinal tract and provide a constant rate of delivery of theoxymorphone.

[0045] When measured by USP Procedure Drug Release USP 23 (incorporatedby reference herein in its entirety), the sustained release formulationsof the invention exhibit an in vitro dissolution rate of about 15% toabout 50% by weight oxymorphone after 1 hour, about 45% to about 80% byweight oxymorphone after 4 hours, and at least about 80% by weightoxymorphone after 10 hours. The in vitro and in vivo releasecharacteristics of the sustained release formulations of the inventionmay be modified using mixtures of one or more different water insolubleand/or water soluble compounds, using different plasticizers, varyingthe thickness of the sustained release film, including providingrelease-modifying compounds in the coating, and/or by providingpassageways through the coating.

[0046] When administered orally to patients the sustained releaseformulations of the invention exhibit the following in vivocharacteristics: (a) a peak plasma level of oxymorphone occurs withinabout 2 to about 6 hours after administration; (b) the duration of theoxymorphone analgesic effect is about 8 to about 24 hours; and (c) therelative oxymorphone bioavailability is about 0.5 to about 1.5 comparedto an orally administered aqueous solution of oxymorphone.

[0047] While the compositions of the invention may be administered asthe sole active pharmaceutical compound in the methods described herein,they can also be used in combination with one or more compounds whichare known to be therapeutically effective against pain.

[0048] The invention also provides pharmaceutical kits comprising one ormore containers filled with one or more of the compositions of theinvention. The kits may further comprise other pharmaceutical compoundsknown in the art to be therapeutically effective against pain, andinstructions for use.

EXAMPLES

[0049] The following examples are for purposes of illustration only andare not intended to limit the scope of the appended claims.

Examples 1 and 2

[0050] Two sustained release delivery systems were prepared by dryblending xanthan gum, locust bean gum, calcium sulfate dehydrate, anddextrose in a high speed mixed/granulator for 3 minutes. A slurry wasprepared by mixing ethyl cellulose with alcohol. While runningchoppers/impellers, the slurry was added to the dry blended mixture, andgranulated for another 3 minutes. The granulation was then dried to aLOD (loss on drying) of less than about 10% by weight. The granulationwas then milled using 20 mesh screen. The relative quantities of theingredients are listed in Table 1. TABLE 1 Sustained Release DeliverySystem Example 1 Example 2 Excipient % % Locust Bean Gum, FCC 25.0 30.0Xanthan Gum, NF 25.0 30.0 Dextrose, USP 35.0 40.0 Calcium SulfateDihydrate, NF 10.0 0.0 Ethylcellulose, NF 5.0 0.0 Alcohol, SD3A(Anhydrous)¹ (10)¹ (20.0)¹ Total 100.0 100.0

Examples 3 to 7

[0051] A series of tablets containing different amounts of oxymorphonehydrochloride were prepared using the sustained release delivery systemof Example 1. The quantities of ingredients per tablet are listed inTable 2. TABLE 2 Ex. 3 Ex. 4 Ex. 5 Ex. 6 Ex. 7 Component mg mg mg mg mgOxymorphone HCl, USP 5 10 20 40 80 Sustained release delivery system 160160 160 160 160 Silicified microcrystalline 20 20 20 20 20 cellulose,N.F. Sodium stearyl fumarate, NF 2 2 2 2 2 Total weight 187 192 202 222262 OPADRY ® (colored) 7.48 7.68 8.08 8.88 10.48 OPADRY ® (clear) 0.940.96 1.01 1.11 1.31

Examples 8 and 9

[0052] Two batches of tablets were prepared as described above forExamples 1-7, using the sustained release delivery system of Example 1.One batch was formulated to provide relatively fast sustained release,the other batch was formulated to provide relatively slow sustainedrelease. Compositions of the tablets are shown in Table 3. TABLE 3Example 8 Example 9 slow release fast release Ingredients mg/tabletmg/tablet Oxymorphone HCl, USP 20 20 Sustained Release Delivery System360 160 Silicified Microcrystalline 20 20 Cellulose, NF Sodium stearylfumarate, NF 4 2 Coating (color) 12.12 12.12 Total weight 416.12 214.12

[0053] The tables of Examples 8 and 9 were tested for in vitro releaserate according to USP Procedure Drug Release USP 23. The results areshown in Table 4. TABLE 4 Example 8 Example 9 Time (hr) slow releasefast release 0.5 18.8% 21.3% 1 27.8% 32.3% 2 40.5% 47.4% 3 50.2% 58.5% 458.1% 66.9% 5 64.7% 73.5% 6 70.2% 78.6% 8 79.0% 86.0% 10 85.3% 90.6% 1289.8% 93.4%

Example 10

[0054] Clinical Study

[0055] A clinical study was conducted to (1) assess the relativebioavailability (rate and extent of absorption) of oxymorphone sustainedrelease (20 mg) (fast release formulation of Example 9) compared to oralsolution oxymorphone (10 mg) under fasted conditions, (2) to assess therelative bioavailability of oxymorphone sustained release (20 mg)compared to oral solution oxymorphone (10 mg) under fed conditions, (3)to assess the relative bioavailability of oxymorphone sustained release(20 mg) fed compared to oxymorphone sustained release (20 mg) fasted,(4) to assess the relative bioavailability of oral solution oxymorphonefed compared to oral solution oxymorphone fasted, and (5) to assess therelative safety and tolerability of sustained release oxymorphone (20mg) under fed and fasted conditions.

[0056] This study had a single-center, open-label, analytically blinded,randomized, four-way crossover design. Subjects randomized to TreatmentA and Treatment C, as described below, were in a fasted state followinga 10-hour overnight fast. Subjects randomized to Treatment B andTreatment D, as described below, were in the fed state, having had ahigh fat meal, completed ten minutes prior to dosing. There was a 14-daywashout interval between the four dose administrations. The subjectswere confined to the clinic during each study period. Subjects assignedto receive Treatment A and Treatment B were discharged from the clinicon Day 3 following the 48-hour procedures, and subjects assigned toreceive Treatment C and Treatment D were discharged from the clinic onDay 2 following the 36-hour procedures. On Day 1 of each study periodthe subjects received one of four treatments:

[0057] Treatments A and B were of oxymorphone sustained release 20 mgtablets. Subjects randomized to Treatment A received a single oral doseof one 20 mg oxymorphone sustained release tablet taken with 240 ml ofwater after a 10-hour fasting period. Subjects randomized to Treatment Breceived a single oral dose of one 20 mg oxymorphone sustained releasetablet taken with 240 ml of water 10 minutes after a standardized highfat meal.

[0058] Treatments C and D were of oxymorphone HCl solutions, USP, 1.5mg/mil injection 10 ml vials. Subjects randomized to Treatment Creceived a single oral dose of 10 mg (6.7 ml) oxymorphone solution takenwith 240 ml of water after a 10-hour fasting period. Subjects randomizedto Treatment D received a single oral dose of 10 mg (6.7 ml) oxymorphonesolution taken with 240 ml of water 10 minutes after a standardizedhigh-fat meal.

[0059] A total of 28 male subjects were enrolled in the study, and 24subjects completed the study. The mean age of the subjects was 27 years(range of 19 through 38 years), the mean height of the subjects was 69.6inches (range of 64.0 through 75.0 inches), and the mean weight of thesubjects was 169.0 pounds (range 117.0 through 202.0 pounds). Thesubjects were not to consume any alcohol-, caffeine-, orxanthine-containing foods or beverages for 24 hours prior to receivingstudy medication for each study period. Subjects were to be nicotine andtobacco free for at least 6 months prior to enrolling in the study. Inaddition, over-the-counter medications were prohibited 7 days prior todosing and during the study. Prescription medications were not allowed14 days prior to dosing and during the study.

[0060] The subjects were screened within 14 days prior to studyenrollment. The screening procedure included medical history, physicalexamination (height, weight, frame size, vital signs, and ECG), andclinical laboratory tests (hematology, serum chemistry, urinalysis, HIVantibody screen, Hepatitis B surface antigen screen, Hepatitis Cantibody screen, and a screen for cannabinoids).

[0061] During the study, the subjects were to remain in an uprightposition (sitting or standing) for 4 hours after the study drug wasadministered. Water was restricted 2 hours predose to 2 hours postdose.During the study, the subjects were not allowed to engage in anystrenuous activity.

[0062] Subjects reported to the clinic on the evening prior to eachdosing. The subjects then observed a 10-hour overnight fast. On Day 1,subjects randomized to Treatment B and Treatment D received a high-fatbreakfast within 30 minutes prior to dosing. A standardized mealschedule was then initiated with lunch 4 hours postdose, dinner 10 hourspostdose, and a snack 13 hours postdose. On Day 2, a standardized mealwas initiated with breakfast at 0815, lunch at 1200, and dinner at 1800.Subjects randomized to Treatment A and Treatment B received a snack at2100 on Day 2.

[0063] Vital signs (sitting for 5 minutes and consisting of bloodpressure, pulse, respiration, and temperature), and 12-lead ECG wereassessed at the −13 hour point of each check-in period and at thecompletion of each period. A clinical laboratory evaluation (hematology,serum chemistry, urinalysis) and a brief physical examination wereperformed at the −13 hour of each check-in period and at the completionof the each period. Subjects were instructed to inform the studyphysician and/or nurses of any adverse events that occurred during thestudy.

[0064] Blood samples (7 ml) were collected during each study period atthe 0 hour (predose), and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 14,16, 20, 24, 30, 36, and 48 hours post-dose (19 samples) for subjectsrandomized to Treatment A and Treatment B. Blood samples (7 mi) werecollected during each study period at the 0 hour (predose), and at 0.25,0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 20, and36 hours post-dose (21 samples) for subjects randomized to Treatment Cand Treatment D. A total of 80 blood samples (560 ml) per subject weredrawn during the study for drug analysis. Plasma samples were separatedby centrifugation, and then frozen at −70° C., and kept frozen untilassayed.

[0065] An LC/MS/MS method was developed and validated for thedetermination of oxymorphone in human EDTA plasma. Samples were spikedwith internal standard, d₃ oxymorphone, and placed on the RapidTrace®(Zymark Corporation, Hopkinton, Mass.) for automatic solid phaseextraction. Extracts were dried under nitrogen and reconstituted withacetonitrile before injection onto an LC/MS/MS. The Perkin Elmer SciexAPI III+, or equivalent, using a turbo ion spray interface was employedin this study. Positive ions were monitored in the MRM mode.

[0066] The pharmacokinetic parameters shown in Table 5 were computedfrom the plasma oxymorphone concentration-time data. TABLE 5 AUC(0-t)Area under the drug concentration-time curve from time zero to the timeof the last quantifiable concentration (Ct), calculated using lineartrapezoidal summation. AUC(0-inf) Area under the drug concentration-timecurve from time zero to infinity. AUC(0-inf) = AUC(0-t) + Ct/Kel, whereKel is the terminal elimination rate constant. AUC(0-24) Partial areaunder the drug concentration-time curve from time zero to 24 hours. CmaxMaximum observed drug concentration. Tmax Time of the observed maximumdrug concentration. Kel Elimination rate constant based on the linearregression of the terminal linear portion of the LN(concentration) timecurve. T1/2el Half life, the time required for the concentration todecline by 50%, calculated as LN(2)/Kel

[0067] Terminal elimination rate constants were computed using linearregression of a minimum of three time points, at least two of which wereconsecutive. Kel values for which correlation coefficients were lessthan or equal to 0.8 were not reported in the pharmacokinetic parametertables or included in the statistical analysis. Thus, T1/2el,AUC(0-inf), C1/F, MRT, and LN-transformed T1/2el, AUC(0-inf), and C1/Fwere also not reported in these cases.

[0068] A parametric (normal-theory) general linear model was applied toeach of the above parameters (excluding Tmax and Frel), and theLN-transformed parameters Cmax, AUC(0-24), AUC(0-t), AUC(0-inf), C1/F,and T1/2el. Initially, the analysis of variance (ANOVA) model includedthe following factors: treatment, sequence, subject within sequence,period, and carryover effect. If carryover effect was not significant,it was dropped from the model. The sequence effect was tested using thesubject within sequence mean square, and all other main effects weretested using the residual error (error mean square). The followingtreatment comparisons of relative rate and extent of absorption weremade: Treatment B versus Treatment A, Treatment A versus Treatment C(dose normalized to 20 mg). Treatment B versus Treatment D (dosenormalized to 20 mg), and Treatment D versus Treatment C (dosenormalized to 20 mg for both treatments). The 90% confidence intervalsof the ratios of the treatment least squares parameter means werecalculated. Tmax was analyzed using the Wilcoxon Signed Ranks test.Summary statistics were presented for Frel.

[0069] Plasma oxymorphone concentrations were listed by subject at eachcollection time and summarized using descriptive statistics.Pharmacokinetic parameters were also listed by subject and summarizedusing descriptive statistics.

[0070] A total of 26 analytical runs were required to process theclinical samples from this study. Of these 26 analytical runs, 26 wereacceptable for oxymorphone. Standard curves for the 26 analytical runsin EDTA plasma used in this study covered a range of 0.0500 to 20.000mg/ml with a limit of quantitation of 0.0500 ng/ml for both compounds.Quality control samples analyzed with each analytical run hadcoefficients of variation less than or equal to 14.23% for oxymorphone.

[0071] A total of 28 subjects received at least one treatment. Onlysubjects who completed all 4 treatments were included in the summarystatistics and statistical analysis.

[0072] The mean oxymorphone plasma concentration versus time curves forTreatments A, B, C, and D are presented in FIG. 1 (linear scale, withoutstandard deviation).

[0073] Individual concentration versus time curves were characterized bymultiple peaks which occurred in the initial 12-hour period followingthe dose. In addition, a small “bump” in plasma oxymorphoneconcentration was generally observed in the 24 to 48 hour post-doseperiod.

[0074] The arithmetic means of the plasma oxymorphone pharmacokineticparameters and the statistical comparisons for Treatment B versusTreatment A are summarized in Table 6. TABLE 6 Summary of thePharmacokinetic Parameters of Plasma Oxymorphone for Treatments B and APlasma Oxymorphone Treatment A Treatment B Pharmacokinetic ArithmeticArithmetic Mean Parameters Mean SD Mean SD 90% CI Ratio Cmax(ng/ml)1.7895 0.6531 1.1410 0.4537 125.4-191.0 158.2 Tmax(hr) 5.65 9.39 5.577.14 Auc(0-24)(ng * hr/ml) 14.27 4.976 11.64 3.869 110.7-134.0 122.3AUC(O-t)(ng * hr/ml) 19.89 6.408 17.71 8.471 100.2-123.6 111.9AUC(O-inf) 21.29 6.559 19.29 5.028 105.3-133.9 119.6 (ng * hr/ml) T1/2el(hr) 12.0 3.64 12.3 3.99  57.4-155.2 106.3

[0075] The arithmetic means of the plasma oxymorphone pharmacokineticparameters and the statistical comparisons for Treatment A versusTreatment C are summarized in Table 7. TABLE 7 Summary of thePharmacokinetic Parameters of Plasma Oxymorphone for Treatments A and CPlasma Oxymorphone Treatment A Treatment C Pharmacokinetic ArithmeticArithmetic Mean Parameters Mean SD Mean SD 90% CI Ratio Cmax(ng/ml)1.1410 0.4537 2.2635 1.0008 33.4-66.0 49.7 Tmax(hr) 5.57 7.14 0.978 1.14Auc(0-24)(ng * hr/ml) 11.64 3.869 12.39 4.116  82.8-104.6 93.7AUC(0-I)(ng * hr/ml 17.71 8.471 14.53 4.909 107.7-136.3 122.0 AUC(0-inf)19.29 5.028 18.70 6.618  80.2-108.4 94.3 (ng * hr/ml) T 1/2el(hr) 12.33.99 16.2 11.4  32.9-102.1 67.5

[0076] The arithmetic means of the plasma oxymorphone pharmacokineticparameters and the statistical comparisons for Treatment D versusTreatment C are summarized in Table 8. TABLE 8 Summary of thePharmacokinetic Parameters of Plasma Oxymorphone for Treatments A and CPlasma Oxymorphone Treatment B Treatment D Pharmacokinetic ArithmeticArithmetic Mean Parameters Mean SD Mean SD 90% CI Ratio Cmax(ng/ml)1.7895 0.6531 3.2733 1.3169 42.7-65.0 50.0 Tmax(hr) 5.65 9.39 1.11 0.768Auc(0-24)(ng * hr/ml) 14.27 4.976 17.30 5.259 74.4-90.1 82.2AUC(0-t)(ng * hr/ml) 19.89 6.408 19.28 6.030  92.5-114.1 103.3AUC(0-inf) 21.29 6.559 25.86 10.03 75.0-95.2 85.1 (ng * hr/ml) T1/2el(hr) 12.0 3.64 20.6 19.3 31.9-86.1 59.0

[0077] The arithmetic means of the plasma oxymorphone pharmacokineticparameters and the statistical comparisons for Treatment D versusTreatment C are summarized in Table 9. TABLE 9 Summary of thePharmacokinetic Parameters of Plasma Oxymorphone for Treatments A and CPlasma Oxymorphone Treatment D Treatment C Pharmacokinetic ArithmeticArithmetic Mean Parameters Mean SD Mean SD 90% CI Ratio Cmax(ng/ml)3.2733 1.3169 2.2635 1.0008 129.7-162.3 146.0 Tmax(hr) 1.11 0.768 0.9781.14 Auc(0-24)(ng * hr/ml) 17.30 5.259 12.39 4.116 128.5-150.3 139.4AUC(0-t)(ng * hr/ml) 19.20 6.030 14.53 4.909 117.9-146.5 132.2AUC(0-inf) 25.86 10.03 18.70 6.618 118.6-146.6 132.6 (ng * hr/ml) T1/2el(hr) 20.6 19.3 16.2 11.4  87.3-155.9 121.6

[0078] The relative bioavailability calculations are summarized in Table10. TABLE 10 Mean (S.D.) Relative Oxymorphone Bioavailability Determinedfrom AUC (0-inf) and AUC (0-24) Frel BA Frel AC Frel BD Frel DCAUC(0-inf) 1.169 (0.2041) 1.040 (0.1874) 0.8863 (0.2569) 1.368 (0.4328)AUC(0-24) 1.299 (0.4638) (0.9598) (0.2151) 0.8344 (0.100) 1.470 (0.3922)

[0079] The objectives of this study were to assess the relativebioavailability of oxymorphone from oxymorphone sustained release (20mg) compared to oxymorphone oral solution (10 mg) under both fasted andfed conditions, and to determine the effect of food on thebioavailability of oxymorphone from the sustained release formulationand from the oral solution.

[0080] The presence of a high fat meal had a substantial effect on theoxymorphone Cmax, but less of an effect on oxymorphone AUC fromoxymorphone sustained release tablets. Least Squares (LS) mean Cmax was58% higher and LS mean AUC(0-t) and AUC(0-inf) were 18% higher for thefed condition (Treatment B) compared to the fasted condition (TreatmentA) based on LN-transformed data. This was consistent with the relativebioavailability determination from AUC (0-inf) since mean Frel was 1.17.Individual Frel values based on AUC (0-24) were similar (less than 20%different) to Frel values based on AUC (0-inf) for all but 2 subjects.Comparison of mean Frel from AUC (0-inf) to mean Frel from AUC (0-24) ismisleading, because not all subjects had a value for AUC (0-inf). MeanTmax values were similar (approximately 5.6 hours), and no significantdifferent in Tmax was shown using nonparametric analysis. Half valuedurations were significantly different between the two treatments.

[0081] The effect of food on oxymorphone bioavailability from the oralsolution was more pronounced, particularly in terms of AUC. LS mean Cmaxwas 50% higher and LS mean AUC(0-t) and AUC(0-inf) were 32-34% higherfor the fed condition (Treatment D) compared to the fasted condition(Treatment C) based on LN-transformed data. This was consistent with therelative bioavailability determination from AUC(0-inf) since mean Frelwas 1.37. Individual Frel values based on AUC(0-24) were similar (lessthan 20% different) to Frel values based on AUC(0-inf.) for all but 5subjects. Comparison of mean Frel from AUC(0-inf) to mean Frel fromAUC(0-24) is misleading because not all subjects had a value forAUC(0-inf). Mean Tmax (approximately 1 hour) was similar for the twotreatments and no significant difference was shown.

[0082] Under fasted conditions, oxymorphone sustained release 20 mgtablets exhibited similar extent of oxymorphone availability compared to10 mg oxymorphone oral solution normalized to a 20 mg dose (Treatment Aversus Treatment C). From LN-transformed data, LS mean AUC(0-t) was 17%higher for oxymorphone sustained release, whereas LS mean AUC(0-inf)values were nearly equal (mean ratio=99%). However, AUC(0-t) is not thebest parameter to evaluate bioavailability since the plasmaconcentrations were measured for 48 hours for the sustained releaseformulation versus 36 hours for the oral solution. Mean Frel valuescalculated from AUC(0-inf) and AUC(0-24), (1.0 and 0.96, respectively)also showed similar extent of oxymorphone availability between the twotreatments.

[0083] There were differences in parameters reflecting rate ofabsorption. LS mean Cmax was 49% lower for oxymorphone sustained releasetablets compared to the dose-normalized oral solution, based onLN-transformed data. Half-value duration was significantly longer forthe sustained release formulation (means, 12 hours versus 2.5 hours).

[0084] Under fed conditions, oxymorphone availability from oxymorphonesustained release 20 mg was similar compared to 10 mg oxymorphone oralsolution normalized to a 20 mg dose (Treatment B versus Treatment D).From LN-transformed data, LS mean AUC(0-inf) was 12% lower foroxymorphone sustained release. Mean Frel values calculated fromAUC(0-inf) and AUC(0-24), (0.89 and 0.83 respectively) also showedsimilar extent of oxymorphone availability from the tablet. There weredifferences in parameters reflecting rate of absorption. LS mean Cmaxwas 46% lower for oxymorphone sustained release tablets compared to thedose-normalized oral solution, based on LN-transformed data. Mean Tmaxwas 5.7 hours for the tablet compared to 1.1 hours for the oralsolution. Half-value duration was significantly longer for the sustainedrelease formulation (means, 7.8 hours versus 3.1 hours).

[0085] The presence of a high fat meal did not appear to substantiallyaffect the availability following administration of oxymorphonesustained release tablets. LS mean ratios were 97% for AUC(0-t) and 91%for Cmax (Treatment B versus A), based on LN-transformed data. This wasconsistent with the relative bioavailability determination fromAUC(0-24), since mean Frel was 0.97. AUC(0-inf) was not a reliablemeasure for bioavailability since half-life could not be estimatedaccurately, and in many cases at all. Half-life estimates were notaccurate because in the majority of subjects, the values for half-lifewere nearly as long or longer (up to 2.8 times longer) as the samplingperiod. Mean Tmax was later for the fed treatment compared to the fastedtreatment (5.2 and 3.6 hours, respectively), and difference wassignificant.

[0086] Under fasted conditions, oxymorphone sustained release 20 mgtablets exhibited similar availability compared to 10 mg oxymorphoneoral solution normalized to a 20 mg dose (Treatment A versus TreatmentC). From LN-transformed data, LS mean ratio for AUC (0-t) was 104.5%.Mean Frel (0.83) calculated from AUC(0-24) also showed similar extent ofoxymorphone availability between the two treatments. There weredifferences in parameters reflecting rate of absorption. LS mean Cmaxwas 57% lower for oxymorphone sustained release tablets compared to thedose-normalized oral solution. Mean Tmax was 3.6 hours for the tabletcompared to 0.88 for the oral solution. Half-value duration wassignificantly longer for the sustained release formulation (means, 11hours versus 2.2 hours).

[0087] Under fed conditions, availability from oxymorphone sustainedrelease 20 mg was similar compared to 10 mg oxymorphone oral solutionnormalized to a 20 mg dose (Treatment B versus Treatment D). FromLN-transformed data, LS mean AUC(0-t) was 14% higher for oxymorphonesustained release. Mean Frel (0.87) calculated from AUC (0-24) alsoindicated similar extent of availability between the treatments. Therewere differences in parameters reflecting rate of absorption. LS meanCmax was 40% lower for oxymorphone sustained release tablets compared tothe dose-normalized oral solution. Mean Tmax was 5.2 hours for thetablet compared to 1.3 hour for the oral solution. Half-value durationwas significantly longer for the sustained release formulation (means,14 hours versus 3.9 hours).

[0088] The extent of oxymorphone availability from oxymorphone sustainedrelease 20 mg tablets was similar under fed and fasted conditions sincethere was less than a 20% difference in LS mean AUC(0-t) and AUC(0-inf)values for each treatment, based on LN-transformed data. Tmax wasunaffected by food; however, LS mean Cmax was increased 58% in thepresence of the high fat meal. Both rate and extent of oxymorphoneabsorption from the oxymorphone oral solution were affected by foodsince LS mean Cmax and AUC values were increased approximately 50 and30%, respectively. Tmax was unaffected by food. Under both fed andfasted conditions, oxymorphone sustained release tablets exhibitedsimilar extent of oxymorphone availability compared to oxymorphone oralsolution since there was less than a 20% difference in LS mean AUC(0-t)and AUC(0-inf) values for each treatment.

[0089] Bioavailability following oxymorphone sustained release 20 mgtablets was also similar under fed and fasted conditions since there wasless than a 20% difference in LS mean Cmax and AUC values for eachtreatment. Tmax was later for the fed condition. The presence of fooddid not affect the extent of availability from oxymorphone oral solutionsince LS mean AUC values were less than 20% different. However, Cmax wasdecreased 35% in the presence of food. Tmax was unaffected by food.Under both fed and fasted conditions, oxymorphone sustained releasetablets exhibited similar extent of availability compared to oxymorphoneoral solution since there was less than a 20% difference in LS mean AUCvalues for each treatment.

[0090] Various modifications of the invention, in addition to thosedescribed herein, will be apparent to one skilled in the art from theforegoing description. Such modifications are intended to fall withinthe scope of the appended claims.

What is claimed is:
 1. A method for making a sustained releaseformulation that comprises oxymorphone or a pharmaceutically acceptablesalt thereof and a sustained release delivery system, wherein thesustained release delivery system comprises a hydrophilic compound, across-linking agent and a pharmaceutical diluent; comprising the stepsof: mixing the hydrophilic compound, the cross-linking agent and thepharmaceutical diluent to form granules; mixing the granules with theoxymorphone or a pharmaceutically acceptable salt thereof to form agranulated composition; and applying pressure to the granulatedcomposition to make the sustained release formulation.
 2. The method ofclaim 1, further comprising applying an outer coating onto at least partof the sustained release formulation.
 3. The method of claim 1, whereinthe oxymorphone or a pharmaceutically acceptable salt thereof and thesustained release delivery system are present in a ratio of from about1:0.5 to about 1:25.
 4. The method of claim 1, wherein the oxymorphoneor pharmaceutically acceptable salt thereof is present in an amount offrom about 1 mg to about 200 mg in the formulation.
 5. The method ofclaim 4, wherein the oxymorphone or pharmaceutically acceptable saltthereof is present in an amount of from about 5 mg to about 80 mg in theformulation.
 6. The method of claim 1, wherein the sustained releasedelivery system is present in an amount of from about 80 mg to about 420mg in the formulation.
 7. The method of claim 6, wherein the sustainedrelease delivery system is present in an amount of from about 80 mg toabout 360 mg in the formulation.
 8. The method of claim 7, wherein thesustained release delivery system is present in an amount of from about80 mg to about 200 mg in the formulation.
 9. The method of claim 1,wherein the hydrophilic compound is present in the sustained releasedelivery system in an amount of from about 20% to about 80% by weight;the cross-linking agent is present in the sustained release deliverysystem in an amount of from about 0.5% to about 80% by weight; and thepharmaceutical diluent is present in the sustained release deliverysystem in an amount of from about 20% to about 80% by weight.
 10. Themethod of claim 9, wherein the hydrophilic compound is present in thesustained release delivery system in an amount of from about 20% toabout 60% by weight; the cross-linking agent is present in the sustainedrelease delivery system in an amount of from about 2% to about 54% byweight; and the pharmaceutical diluent is present in the sustainedrelease delivery system in an amount of from about 20% to about 80% byweight.
 11. The method of claim 10, wherein the hydrophilic compound ispresent in the sustained release delivery system in an amount of fromabout 40% to about 60% by weight; the cross-linking agent is present inthe sustained release delivery system in an amount of from about 20% toabout 30% by weight; and the pharmaceutical diluent is present in thesustained release delivery system in an amount of from about 40% toabout 80% by weight.
 12. The method of claim 1, wherein the hydrophiliccompound is a heteropolysaccharide gum.
 13. The method of claim 1,wherein the hydrophilic compound is selected from xanthan gum,tragacanth gum, a pectin, acacia, karaya, agar, carrageenan, and agellan gum.
 14. The method of claim 1, wherein the hydrophilic compoundis a xanthan gum or a derivative thereof.
 15. The method of claim 1,wherein the cross-linking agent is a homopolysaccharide gum.
 16. Themethod of claim 15, wherein the homopolysaccharide gum is a locust beangum or a guar gum.
 17. The method of claim 1, wherein the pharmaceuticaldiluent selected from starch, lactose, dextrose, sucrose,microcrystalline cellulose, sorbitol, xylitol, and fructose.
 18. Themethod of claim 1, wherein the ratio of the hydrophilic compound to thecross-linking agent is from about 1:9 to about 9:1.
 19. The method ofclaim 1, wherein the ratio of the pharmaceutical diluent to thehydrophilic compound is from about 1:8 to about 8:1.
 20. The method ofclaim 1, wherein the sustained release delivery system further comprisesa hydrophobic polymer.
 21. The method of claim 20, wherein thehydrophobic polymer is present in the sustained release delivery systemin an amount of from about 0.5% to about 20% by weight.
 22. The methodof claim 21, wherein the hydrophobic polymer is present in the sustainedrelease delivery system in an amount of from about 2% to about 10% byweight.
 23. The method of claim 23, wherein the hydrophobic polymer isselected from an alkylcellulose, a hydrophobic cellulosic material, apolyvinyl acetate polymer, a polymer or copolymer of acrylic andmethacrylic acid esters, zein, a wax, a shellac and a hydrogenatedvegetable oil.
 24. The method of claim 20, wherein the alkyl celluloseis ethyl cellulose.
 25. The method of claim 1, wherein the sustainedrelease delivery system further comprises a cationic cross-linkingcompound.
 26. The method of claim 25, wherein the cationic cross-linkingcompound is present in the sustained release delivery system in anamount of from about 0.5% to about 30% by weight.
 27. The method ofclaim 26, wherein the cationic cross-linking compound is present in thesustained release delivery system in an amount of about 5% to about 20%by weight.
 28. The method of claim 25, wherein the cationiccross-linking compound is selected from a monovalent metal cation, amultivalent metal cation, and an inorganic salt.
 29. The method of claim28, wherein the cationic cross-linking agent is an inorganic saltselected from an alkali metal sulfate, an alkali metal chloride, analkali metal borate, an alkali metal bromide, an alkali metal citrate,an alkali metal acetate, an alkali metal lactate, an alkaline earthmetal sulfate, an alkaline earth metal chloride, an alkaline earth metalborate, an alkaline earth metal bromide, an alkaline earth metalcitrate, an alkaline earth metal acetate, an alkaline earth metallactate, and a mixture thereof.
 30. The method of claim 25, wherein thecationic cross-linking compound is selected from calcium sulfate, sodiumchloride, potassium sulfate, sodium carbonate, lithium chloride,tripotassium phosphate, sodium borate, potassium bromide, potassiumfluoride, sodium bicarbonate, calcium chloride, magnesium chloride,sodium citrate, sodium acetate, calcium lactate, magnesium sulfate, andsodium fluoride.
 31. The method of claim 1, wherein the sustainedrelease formulation has an in vitro dissolution rate of from about 15%to about 50% by weight oxymorphone after about 1 hour.
 32. The method ofclaim 1, wherein the sustained release formulation has as in vitrodissolution rate of from about 45% to about 80% by weight oxymorphoneafter about 4 hours.
 33. The method of claim 1, wherein the sustainedrelease formulation has as in vitro dissolution rate of at least about80% by weight oxymorphone after about 10 hours.
 34. The method of claim2, wherein the outer coating comprises a hydrophobic polymer.
 35. Themethod of claim 34, wherein the hydrophobic polymer is a compoundselected from an alkyl cellulose, a hydrophobic cellulosic material, apolyvinyl acetate polymer, a polymer or copolymer of acrylic andmethacrylic acid esters, zein, a wax, a shellac and a hydrogenatedvegetable oil.
 36. The method of claim 34, wherein the hydrophobicpolymer is present on the sustained release formulation to a weight gainfrom about 1% to about 20% by weight of the uncoated tablet.
 37. Themethod of claim 2, wherein the outer coating comprises a plasticizer.38. A method for making a sustained release formulation that comprisesoxymorphone or a pharmaceutically acceptable salt thereof and asustained release delivery system, wherein the sustained releasedelivery system comprises a hydrophilic compound, a cationiccross-linking compound, and a pharmaceutical diluent; comprising thesteps of: mixing the hydrophilic compound, the cationic cross-linkingcompound and the pharmaceutical diluent to form granules; mixing thegranules with the oxymorphone or a pharmaceutically acceptable saltthereof to form a granulated composition; and applying pressure to thegranulated composition to make the sustained release formulation. 39.The method of claim 38, further comprising applying an outer coatingonto at least part of the sustained release formulation.
 40. The methodof claim 38, wherein the ratio of oxymorphone or a pharmaceuticallyacceptable salt thereof to the sustained release delivery system is fromabout 1:0.5 to about 1:25.
 41. The method of claim 38, wherein theoxymorphone or pharmaceutically acceptable salt thereof is present in anamount of from about 1 mg to about 200 mg in the formulation.
 42. Themethod of claim 41, wherein the oxymorphone or pharmaceuticallyacceptable salt thereof is present in an amount of from about 5 mg toabout 80 mg in the formulation.
 43. The method of claim 38, wherein thesustained release delivery system is present in an amount of from about80 mg to about 420 mg in the formulation.
 44. The method of claim 43,wherein the sustained release delivery system is present in an amount offrom about 80 mg to about 360 mg in the formulation.
 45. The method ofclaim 44, wherein the sustained release delivery system is present in anamount of from about 80 mg to about 200 mg in the formulation.
 46. Themethod of claim 38, wherein the hydrophilic compound is present in thesustained release delivery system in an amount of from about 20% toabout 80% by weight; the cationic cross-linking agent is present in thesustained release delivery system in an amount of from about 0.5% toabout 30% by weight; and the pharmaceutical diluent is present in thesustained release delivery system in an amount of from about 20% toabout 80% by weight.
 47. The method of claim 46, wherein the hydrophiliccompound is present in the sustained release delivery system in anamount of from about 20% to about 60% by weight; the cationiccross-linking agent is present in the sustained release delivery systemin an amount of from about 5% to about 20% by weight; and thepharmaceutical diluent is present in the sustained release deliverysystem in an amount of from about 20% to about 80% by weight.
 48. Themethod of claim 47, wherein the hydrophilic compound is present in thesustained release delivery system in an amount of from about 40% toabout 60% by weight; the cationic cross-linking agent is present in thesustained release delivery system in an amount of from about 5% to about20% by weight; and the pharmaceutical diluent is present in thesustained release delivery system in an amount of from about 40% toabout 80% by weight.
 49. The method of claim 38, wherein the hydrophiliccompound is a heteropolysaccharide gum.
 50. The method of claim 38,wherein the hydrophilic compound is compound selected from xanthan gum,tragacanth gum, a pectin, acacia, karaya, agar, carrageenan, and agellan gum.
 51. The method of claim 38, wherein the hydrophilic compoundis a xanthan gum or a derivative thereof.
 52. The method of claim 38,wherein the cationic cross-linking compound is selected from amonovalent metal cation, a multivalent metal cation, and an inorganicsalt.
 53. The method of claim 52, wherein the cationic cross-linkingcompound is an inorganic salt selected from an alkali metal sulfate, analkali metal chloride, an alkali metal borate, an alkali metal bromide,an alkali metal citrate, an alkali metal acetate, an alkali metallactate, an alkaline earth metal sulfate, an alkaline earth metalchloride, an alkaline earth metal borate, an alkaline earth metalbromide, an alkaline earth metal citrate, an alkaline earth metalacetate, an alkaline earth metal lactate, or a mixture thereof.
 54. Themethod of claim 38, wherein the cationic cross-linking compound isselected from calcium sulfate, sodium chloride, potassium sulfate,sodium carbonate, lithium chloride, tripotassium phosphate, sodiumborate, potassium bromide, potassium fluoride, sodium bicarbonate,calcium chloride, magnesium chloride, sodium citrate, sodium acetate,calcium lactate, magnesium sulfate, sodium fluoride, and mixturesthereof.
 55. The method of claim 38, wherein the pharmaceutical diluentis selected from starch, lactose, dextrose, sucrose, microcrystallinecellulose, sorbitol, xylitol, and fructose.
 56. The method of claim 38,wherein the sustained release delivery system further comprises ahydrophobic polymer.
 57. The method of claim 56, wherein the hydrophobicpolymer is present in the sustained release delivery system in an amountof from about 0.5% to about 20% by weight.
 58. The method of claim 57,wherein the hydrophobic polymer is present in the sustained releasedelivery system in an amount of from about 2% to about 10% by weight.59. The method of claim 56, wherein the hydrophobic polymer is selectedfrom an alkyl cellulose, a polyvinyl acetate polymer, a polymer orcopolymer derived from acrylic and methacrylic acid esters, zein, a wax,shellac and a hydrogenated vegetable oil.
 60. The method of claim 59,wherein the hydrophobic polymer is an alkyl cellulose and the alkylcellulose is ethyl cellulose.
 61. The method of claim 38, wherein thesustained release formulation has an in vitro dissolution rate of fromabout 15% to about 50% by weight oxymorphone after about 1 hour.
 62. Themethod of claim 38, wherein the-sustained release formulation has as invitro dissolution rate of about 45% to about 80% by weight oxymorphoneafter about 4 hours.
 63. The method of claim 38, wherein the sustainedrelease formulation has as in vitro dissolution rate of at least about80% by weight oxymorphone after about 10 hours.
 64. The method of claim39, wherein the outer coating comprises a hydrophobic polymer.
 65. Themethod of claim 64, wherein the hydrophobic polymer is selected from analkyl cellulose, a hydrophobic cellulosic material, a polyvinyl acetatepolymer, a polymer or copolymer of acrylic and methacrylic acid esters,zein, a wax, a shellac and a hydrogenated vegetable oil.
 66. The methodof claim 64, wherein the hydrophobic polymer is present on the sustainedrelease formulation to a weight gain from about 1% to about 20% byweight of the uncoated table.
 67. The method of claim 39, wherein theouter coating comprises a plasticizer.
 68. A method for making asustained release formulation that comprises from about 5 to about 80 mgoxymorphone hydrochloride and about 80 mg to about 360 mg of a sustainedrelease delivery system; wherein the sustained release delivery systemcomprises about 8.3% to about 41.7% by weight locust bean gum, about8.3% to about 41.7% by weight xanthan gum, about 20% to about 55% byweight dextrose, about 5% to about 20% by weight calcium sulfatedihydrate, and about 2% to about 10% ethyl cellulose; comprising thesteps of: mixing the locust bean gum, the xanthan gum, the dextrose, thecalcium sulfate, and the ethyl cellulose to form granules; mixing thegranules with the oxymorphone hydrochloride to form a granulatedcomposition; and applying pressure to the granulated composition to makethe sustained release formulation.
 69. The method of claim 68, furthercomprising applying an outer coating onto at least part of the sustainedrelease formulation.
 70. The method of claim 68, comprising about 20 mgoxymorphone hydrochloride.
 71. The method of claim 68, comprising about160 mg of a sustained release delivery system.
 72. The method of claim68, wherein the sustained release delivery system comprises about 25%locust bean gum, about 25% xanthan gum, about 35% dextrose, about 10%calcium sulfate dihydrate, and about 5% ethyl cellulose.
 73. A methodfor making a sustained release formulation that comprises from about 5to about 80 mg oxymorphone hydrochloride and about 300 mg to about 420mg of a sustained release delivery system; wherein the sustained releasedelivery system comprises about 8.3% to 41.7% by weight locust bean gum,about 8.3% to about 41.7% by weight xanthan gum, about 20% to about 55%by weight dextrose, about 5% to about 20% by weight calcium sulfatedihydrate, and about 2% to about 10% ethyl cellulose; comprising thesteps of: mixing the locust bean gum, the xanthan gum, the dextrose, thecalcium sulfate, and the ethyl cellulose to form granules; mixing thegranules with the oxymorphone hydrochloride to form a granulatedcomposition; and applying pressure to the granulated composition to makethe sustained release formulation.
 74. The method of claim 73, furthercomprising applying an outer coating onto at least part of the sustainedrelease formulation.
 75. The method of claim 73, comprising about 20 mgoxymorphone hydrochloride.
 76. The method of claim 73, comprising about360 mg of a sustained release delivery system.
 77. The method of claim73, wherein the sustained release delivery system comprises about 25%locust bean gum, about 25% xanthan gum, about 35% dextrose, about 10%calcium sulfate dihydrate, and about 5% ethyl cellulose.